Extracellular Matrix Encasement Structures and Methods

ABSTRACT

A bioremodelable pouch formed from at least one sheet of bioremodelable extracellular matrix (ECM) material, the pouch including an internal region that is configured to receive a medical device, the pouch including an outer coating comprising a pharmacological agent or ECM-mimicking biomaterial composition comprising poly(glycerol sebacate) (PGS).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No. 13/896,424, which is a continuation-in-part of U.S. application Ser. No. 13/573,566, filed on Sep. 24, 2012, now U.S. Pat. No. 9,066,993, which is a continuation-in-part of U.S. application Ser. No. 13/033,102, filed on Feb. 23, 2011, now U.S. Pat. No. 8,758,448, which is a continuation of application Ser. No. 12/394,914, filed on Feb. 27, 2009, now abandoned, which is a continuation of application Ser. No. 11/747,004, filed on May 10, 2007, now abandoned.

FIELD OF THE INVENTION

The present invention relates to implantable devices. More particularly, the present invention relates to implantable structures and devices; particularly, medical devices, encased in extracellular matrix (ECM) based pouches and/or include ECM based coatings that effectuate modulated healing of damaged tissue and regeneration of new tissue structures with site-specific structural and functional properties.

BACKGROUND OF THE INVENTION

As is well known in the art, treatment of various medical conditions commonly involves implantation of medical devices and/or insertion of medical instruments into a body. Illustrative is the implantation or deployment of heart valves to regulate the flow of blood through cardiovascular vessels, and pacemakers to control abnormal heart rhythms.

Implantable medical devices; particularly, cardiovascular implants, have unique blood biocompatibility requirements to ensure that the device is not rejected (as in the case of natural tissue materials for heart valves and grafts for heart transplants) or that adverse thrombogenic (clotting) or hemodynamic (blood flow) responses are avoided.

Several cardiovascular implants, such as heart valves, are formed from natural tissue. Illustrative are the heart valves disclosed in U.S. Pat. Nos. 6,719,788 and 5,480,424 to Cox. The disclosed bioprostheses can, however, be affected by gradual calcification, which can, and in many instances will, lead to the eventual stiffening and tearing of the implant.

Many non-bioprosthetic implants are, however, fabricated from various metals and polymeric materials, and other exotic materials, such as pyrolytic carbon-coated graphite.

For example, pacemakers, defibrillators, leads, and other similar cardiovascular implants are often fabricated from Ni—Co—Cr alloy, Co—Cr—Mo alloy, titanium, and Ti-6Al-4V alloy, stainless steel, and various biocompatible polymeric materials. Artificial heart valves are often fabricated from various combinations of nylon, silicone, titanium, Teflon™, polyacetal, graphite and pyrolytic carbon.

Artificial hearts and ventricular assist devices are often fabricated from various combinations of stainless steel, cobalt alloy, titanium, Ti-6Al-4V alloy, carbon fiber reinforced composites, polyurethanes, Biolon™, Hemothane™, Dacron™, polysulfone, and other thermoplastics.

Finally, catheters and guide wires are often fabricated from Co—Ni or stainless steel wire. In many instances, the wire is encased in a polymeric material.

As is well known in the art, several major problems are often encountered when a medical device (or other device, e.g., tracking apparatus) fabricated from one of the aforementioned materials is implanted in the body. A major problem that is often encountered after implantation of such a device in the body is inflammation of surrounding tissue.

Another major problem is the high incidence of infection.

A further problem that is often encountered after implantation of the medical device in the body is the formation of blood clots (thrombogenesis).

One additional problem that is also often encountered is the degradation, e.g., corrosion, of medical device leads and, thereby, premature failure of the device after implantation in the body.

Most medical devices are designed to be implanted in the body for an extended period of time. However, when a harsh biological response (or premature failure of the device) is encountered after implantation, it is often necessary to remove the device through a secondary surgical procedure, which can, and in many instances will, result in undesirable pain and discomfort to the patient, and possibly additional trauma to the adjacent tissue. In addition to the pain and discomfort, the patient must be subjected to an additional time consuming and complicated surgical procedure with the attendant risks of surgery.

There is thus a need to provide medical devices that are configured for implantation in the body, and substantially reduce or eliminate the harsh biological responses associated with conventional implanted medical devices, including inflammation, infection and thrombogenesis.

It is therefore an object of the present invention to provide encasement structures that are configured to encase a medical device therein and substantially reduce or eliminate the harsh biological responses associated with conventional implanted medical devices, including inflammation, infection and thrombogenesis, when implanted in the body.

It is another object of the present invention to provide encasement structures that are configured to encase a medical device therein, and effectively improve biological functions and/or promote modulated healing of adjacent tissue and the growth of new tissue when implanted in the body.

It is another object of the present invention to provide encasement structures that are configured to encase a medical device therein and administer one or more pharmacological or therapeutic agents when implanted in the body.

It is yet another object of the present invention to provide medical devices that are configured for insertion or implantation in the body and exhibit enhanced biocompatibility and hemocompatibility when inserted or implanted therein.

SUMMARY OF THE INVENTION

The present invention is directed to encasement structures and compositions for encasing devices; particularly, medical devices.

In a preferred embodiment of the invention, the encasement structures comprise extracellular matrix (ECM) encasement structures and compositions.

In a preferred embodiment, the encasement structures comprise a pocket or pouch that is configured to receive a device therein.

In some embodiments, the device comprises a medical device. According to the invention, the medical device can comprise, without limitation, a pacemaker, defibrillator, synthetic heart valve, ventricular assist device, artificial heart, physiological sensor, catheter, and associated components, e.g., the electrical leads and lines associated therewith.

In some embodiments, the encasement structures are configured to encase an entire medical device.

In some embodiments, the encasement structures are also configured to encase at least a portion of the medical device electrical leads.

In a preferred embodiment, the encasement structures comprise (or are constructed of) a bioremodelable member comprising a bioremodelable composition that includes at least one ECM material. In some embodiments of the invention, the encasement structures comprise a plurality of bioremodelable members.

According to the invention, the bioremodelable member can comprise a substantially solid or mesh structure.

In some embodiments of the invention, the bioremodelable member(s) comprises at least one coating or layer.

In some embodiments of the invention, the coating comprises a pharmacological agent or composition.

In some embodiments of the invention, the coating comprises an ECM composition comprising at least one ECM material.

In some embodiments of the invention, the coating comprises a polymeric material composition.

In other embodiments of the invention, there are provided medical devices that are encased in an encasement structure of the invention and configured for insertion or implantation in the body.

In other embodiments of the invention, there are provided medical devices that include at least one coating of an ECM composition; the ECM composition similarly including at least one ECM material.

In a preferred embodiment, the ECM material referenced above comprises mammalian extracellular matrix tissue selected from the group comprising small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), central nervous system tissue, epithelium of mesodermal origin, i.e. mesothelial tissue, dermal extracellular matrix, subcutaneous extracellular matrix, gastrointestinal extracellular matrix, i.e. large and small intestines, tissue surrounding growing bone, placental extracellular matrix, ornamentum extracellular matrix, cardiac extracellular matrix, e.g., pericardium and/or myocardium, kidney extracellular matrix, pancreas extracellular matrix, lung extracellular matrix, and combinations thereof.

In some embodiments of the invention, the ECM material and, hence ECM encasement structures and coatings formed therefrom, include at least one additional biologically active agent or composition, i.e. an agent that induces or modulates a physiological or biological process, or cellular activity, e.g., induces proliferation, and/or growth and/or regeneration of tissue.

In some embodiments of the invention, the biologically active agent comprises a growth factor selected from the group comprising transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β), fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor (bFGF), and vascular epithelial growth factor (VEGF).

In some embodiments, the biologically active agent comprises a cell selected from the group comprising a stem cell, cardiomyocyte, myofibroblast, mesenchymal stem cell, exogenous cell, endogenous cell, progenitor cell and macrophage.

In some embodiments of the invention, the ECM material and, hence ECM encasement structures and coatings formed therefrom, include at least one pharmacological agent or composition (or drug), i.e. an agent or composition that is capable of producing a desired biological effect in vivo, e.g., stimulation or suppression of apoptosis, stimulation or suppression of an immune response, etc.

In some embodiments, the pharmacological agent or composition is selected from the group comprising an antibiotic, antifungal agent, anti-viral agent, anticoagulant, antithrombic agent and anti-inflammatory.

In some embodiments, the pharmacological agent comprises a statin, i.e. a HMG-CoA reductase inhibitor, selected from the group comprising atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.

According to the invention, upon implanting an encased or coated medical device of the invention in a subject, modulated healing and regeneration of tissue structures with site-specific structural and functional properties are induced.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features and advantages will become apparent from the following and more particular description of the preferred embodiments of the invention, as illustrated in the accompanying drawings, and in which like referenced characters generally refer to the same parts or elements throughout the views, and in which:

FIG. 1 is a perspective view of a biventricular (Bi-V) pacemaker;

FIG. 2A is a perspective view of one embodiment of a bioremodelable member, in accordance with the invention;

FIG. 2B is a perspective view of another embodiment of a bioremodelable member, in accordance with the invention;

FIG. 3 is a front plan view of the bioremodelable member shown in FIG. 2A having a coating disposed on the top surface thereof, in accordance with the invention;

FIG. 4 is a front plan view of the bioremodelable member shown in FIG. 2A having a coating disposed on the entire outer surface, in accordance with the invention;

FIG. 5 is a perspective view of the bioremodelable member shown in FIG. 2A, illustrating a folded pre-lamination configuration of an encasement structure, in accordance with the invention;

FIG. 6 is a top plan view of another embodiment of a bioremodelable member, in accordance with the invention;

FIG. 7 is a perspective view of the bioremodelable member shown in FIG. 6, illustrating a folded pre-lamination configuration of an encasement structure, in accordance with the invention;

FIG. 8 is a perspective view of the biventricular (Bi-V) pacemaker shown in FIG. 1 encased in an encasement structure formed with the bioremodelable member shown in FIG. 6, in accordance with the invention;

FIG. 9 is a front, partial sectional plan view of the encasement structure/biventricular (Bi-V) pacemaker assembly shown in FIG. 8, in accordance with the invention;

FIG. 10 is a front, partial sectional plan view of one embodiment of a multi-bioremodelable member encasement structure having the biventricular (Bi-V) pacemaker shown in FIG. 1 encased therein, in accordance with the invention;

FIG. 11 is a perspective view of the biventricular (Bi-V) pacemaker shown in FIG. 1 having coating disposed thereon, in accordance with the invention; and

FIG. 12 is a front, partial sectional plan view of the coated biventricular (Bi-V) pacemaker shown in FIG. 11, in accordance with the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

Before describing the present invention in detail, it is to be understood that this invention is not limited to particularly exemplified apparatus, systems, structures or methods as such may, of course, vary. Thus, although a number of apparatus, systems and methods similar or equivalent to those described herein can be used in the practice of the present invention, the preferred apparatus, systems, structures and methods are described herein.

It is also to be understood that, although the present invention is described and illustrated in connection with encased medical devices, the invention is not limited to medical devices. According to the invention, the extracellular matrix (ECM) structures and compositions of the invention can also be employed to encase other devices, including, by way of example, a sensor or tracking device.

It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments of the invention only and is not intended to be limiting.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one having ordinary skill in the art to which the invention pertains.

Further, all publications, patents and patent applications cited herein, whether supra or infra, are hereby incorporated by reference in their entirety.

As used in this specification and the appended claims, the singular forms “a, “an” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “an active” includes two or more such actives and the like.

Further, ranges can be expressed herein as from “about” or “approximately” one particular value, and/or to “about” or “approximately” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about” or “approximately”, it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” or “approximately” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “approximately 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed then “less than or equal to 10” as well as “greater than or equal to 10” is also disclosed.

DEFINITIONS

The term “medical device”, as used herein, means and includes a therapeutic, surgical or prosthetic device configured for insertion or implantation in the body of a warm blooded mammal, including humans and primates; avians; domestic household or farm animals, such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like. The term “medical device” thus includes, without limitation, a pacemaker, defibrillator, synthetic heart valve, ventricular assist device, artificial heart, physiological sensor, catheter, and associated components thereof, including electrical leads and lines associated therewith.

The terms “extracellular matrix”, “ECM” and “ECM material” are used interchangeably herein, and mean and include a collagen-rich substance that is found in between cells in mammalian tissue, and any material processed therefrom, e.g. decellularized ECM. According to the invention, the ECM material can be derived from a variety of mammalian tissue sources, including, without limitation, small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), central nervous system tissue, epithelium of mesodermal origin, i.e. mesothelial tissue, dermal extracellular matrix, subcutaneous extracellular matrix, gastrointestinal extracellular matrix, i.e. large and small intestines, tissue surrounding growing bone, placental extracellular matrix, ornomentum extracellular matrix, cardiac extracellular matrix, e.g., pericardium and/or myocardium, kidney extracellular matrix, pancreas extracellular matrix, lung extracellular matrix, and combinations thereof.

The ECM material can also comprise collagen from mammalian sources.

The terms “urinary bladder submucosa (UBS)”, “small intestine submucosa (SIS)” and “stomach submucosa (SS)” also mean and include any UBS and/or SIS and/or SS material that includes the tunica mucosa (which includes the transitional epithelial layer and the tunica propria), submucosal layer, one or more layers of muscularis, and adventitia (a loose connective tissue layer) associated therewith.

The ECM material can also be derived from basement membrane of mammalian tissue/organs, including, without limitation, urinary basement membrane (UBM), liver basement membrane (LBM), and amnion, chorion, allograft pericardium, allograft acellular dermis, amniotic membrane, Wharton's jelly, and combinations thereof.

Additional sources of mammalian basement membrane include, without limitation, spleen, lymph nodes, salivary glands, prostate, pancreas and other secreting glands.

The ECM material can also be derived from other sources, including, without limitation, synthesized extracellular matrices, i.e. cell cultures.

The term “angiogenesis”, as used herein, means a physiologic process involving the growth of new blood vessels from pre-existing blood vessels.

The term “neovascularization”, as used herein, means and includes the formation of functional vascular networks that can be perfused by blood or blood components. Neovascularization includes angiogenesis, budding angiogenesis, intussuceptive angiogenesis, sprouting angiogenesis, therapeutic angiogenesis and vasculogenesis.

The terms “biologically active agent” and “biologically active composition” are used interchangeably herein, and mean and include agent that induces or modulates a physiological or biological process, or cellular activity, e.g., induces proliferation, and/or growth and/or regeneration of tissue.

The terms “biologically active agent” and “biologically active composition” thus mean and include, without limitation, the following growth factors: platelet derived growth factor (PDGF), epidermal growth factor (EGF), transforming growth factor alpha (TGF-alpha), transforming growth factor beta (TGF-beta), fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor (bFGF), vascular epithelial growth factor (VEGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), nerve growth factor (NGF), platlet derived growth factor (PDGF), tumor necrosis factor alpha (TNA-alpha), and placental growth factor (PLGF).

The terms “biologically active agent” and “biologically active composition” also mean and include, without limitation, human embryonic stem cells, fetal cardiomyocytes, myofibroblasts, mesenchymal stem cells, autotransplated expanded cardiomyocytes, adipocytes, totipotent cells, pluripotent cells, blood stem cells, adult stem cells, bone marrow cells, embryonic stem cells, parenchymal cells, epithelial cells, endothelial cells, mesothelial cells, fibroblasts, osteoblasts, chondrocytes, exogenous cells, endogenous cells, stem cells, hematopoietic stem cells, bone-marrow derived progenitor cells, myocardial cells, skeletal cells, fetal cells, undifferentiated cells, multi-potent progenitor cells, unipotent progenitor cells, monocytes, cardiac myoblasts, skeletal myoblasts, macrophages, capillary endothelial cells, analogous cells, xenogenic cells, allogenic cells, and post-natal stem cells.

The terms “biologically active agent” and “biologically active composition” also mean and include, without limitation, the following biologically active agents (referred to interchangeably herein as a “protein”, “peptide” and “polypeptide”): collagen (types I-V), proteoglycans, glycosaminoglycans (GAGs), glycoproteins, growth factors, cytokines, cell-surface associated proteins, cell adhesion molecules (CAM), angiogenic growth factors, endothelial ligands, matrikines, cadherins, immuoglobins, fibril collagens, non-fibrallar collagens, basement membrane collagens, multiplexins, small-leucine rich proteoglycans, decorins, biglycans, fibromodulins, keratocans, lumicans, epiphycans, heparin sulfate proteoglycans, perlecans, agrins, testicans, syndecans, glypicans, serglycins, selectins, lecticans, aggrecans, versicans, neurocans, brevicans, cytoplasmic domain-44 (CD-44), macrophage stimulating factors, amyloid precursor proteins, heparins, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate A, heparin sulfates, hyaluronic acids, fibronectins, tenascins, elastins, fibrillins, laminins, nidogen/enactins, fibulin I, fibulin II, integrins, transmembrane molecules, thrombospondins, ostepontins, and angiotensin converting enzymes (ACE).

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” are used interchangeably herein, and mean and include an agent, drug, compound, composition of matter or mixture thereof, including its formulation, which provides some therapeutic, often beneficial, effect. This includes any physiologically or pharmacologically active substance that produces a localized or systemic effect or effects in animals, including warm blooded mammals, humans and primates; avians; domestic household or farm animals, such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” thus mean and include, without limitation, antibiotics, anti-arrhythmic agents, anti-viral agents, analgesics, steroidal anti-inflammatories, non-steroidal anti-inflammatories, anti-neoplastics, anti-spasmodics, modulators of cell-extracellular matrix interactions, proteins, hormones, growth factors, matrix metalloproteinases (MMPS), enzymes and enzyme inhibitors, anticoagulants and/or antithrombic agents, DNA, RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, polypeptides, oligonucleotides, polynucleotides, nucleoproteins, compounds modulating cell migration, compounds modulating proliferation and growth of tissue, and vasodilating agents.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” thus include, without limitation, atropine, tropicamide, dexamethasone, dexamethasone phosphate, betamethasone, betamethasone phosphate, prednisolone, triamcinolone, triamcinolone acetonide, fluocinolone acetonide, anecortave acetate, budesonide, cyclosporine, FK-506, rapamycin, ruboxistaurin, midostaurin, flurbiprofen, suprofen, ketoprofen, diclofenac, ketorolac, nepafenac, lidocaine, neomycin, polymyxin b, bacitracin, gramicidin, gentamicin, oyxtetracycline, ciprofloxacin, ofloxacin, tobramycin, amikacin, vancomycin, cefazolin, ticarcillin, chloramphenicol, miconazole, itraconazole, trifluridine, vidarabine, ganciclovir, acyclovir, cidofovir, ara-amp, foscarnet, idoxuridine, adefovir dipivoxil, methotrexate, carboplatin, phenylephrine, epinephrine, dipivefrin, timolol, 6-hydroxydopamine, betaxolol, pilocarpine, carbachol, physostigmine, demecarium, dorzolamide, brinzolamide, latanoprost, sodium hyaluronate, insulin, verteporfin, pegaptanib, ranibizumab, and other antibodies, antineoplastics, anti-VGEFs, ciliary neurotrophic factor, brain-derived neurotrophic factor, bFGF, Caspase-1 inhibitors, Caspase-3 inhibitors, α-Adrenoceptors agonists, NMDA antagonists, Glial cell line-derived neurotrophic factors (GDNF), pigment epithelium-derived factor (PEDF), and NT-3, NT-4, NGF, IGF-2.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” further mean and include the following Class I-Class V antiarrhythmic agents: (Class Ia) quinidine, procainamide and disopyramide; (Class Ib) lidocaine, phenytoin and mexiletine; (Class Ic) flecainide, propafenone and moricizine; (Class II) propranolol, esmolol, timolol, metoprolol and atenolol; (Class III) amiodarone, sotalol, ibutilide and dofetilide; (Class IV) verapamil and diltiazem) and (Class V) adenosine and digoxin.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” further mean and include, without limitation, the following antiobiotics: aminoglycosides, cephalosporins, chloramphenicol, clindamycin, erythromycins, fluoroquinolones, macrolides, azolides, metronidazole, penicillins, tetracyclines, trimethoprim-sulfamethoxazole and vancomycin.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” further include, without limitation, the following steroids: andranes (e.g., testosterone), cholestanes, cholic acids, corticosteroids (e.g., dexamethasone), estraenes (e.g., estradiol) and pregnanes (e.g., progesterone).

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” can further include one or more classes of narcotic analgesics, including, without limitation, morphine, codeine, heroin, hydromorphone, levorphanol, meperidine, methadone, oxycodone, propoxyphene, fentanyl, methadone, naloxone, buprenorphine, butorphanol, nalbuphine and pentazocine.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” can further include one or more classes of topical or local anesthetics, including, without limitation, esters, such as benzocaine, chloroprocaine, cocaine, cyclomethycaine, dimethocaine/larocaine, piperocaine, propoxycaine, procaine/novacaine, proparacaine, and tetracaine/amethocaine. Local anesthetics can also include, without limitation, amides, such as articaine, bupivacaine, cinchocaine/dibucaine, etidocaine, levobupivacaine, lidocaine/lignocaine, mepivacaine, prilocaine, ropivacaine, and trimecaine. Local anesthetics can further include combinations of the above from either amides or esters.

The terms “pharmacological agent”, “active agent”, “drug” and “active agent formulation” can further include one or more classes of cytotoxic anti-neoplastic agents or chemotherapy agents, including, without limitation, alkylating agents, cisplatin, carboplatin, oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil, and ifosfamide.

Chemotherapy agents can also include, without limitation, antimetabolites, such as purine analogues, pyrimidine analogues and antifolates, plant alkaloids, such as vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin, etoposide and teniposide, taxanes, such as paclitaxel and docetaxel, topoisomerase inhibitors, such as irinotecan, topotecan, amsacrine, etoposide, etoposide phosphate and teniposide, cytotoxic antibiotics, such as actinomyocin, bleomycin, plicamycin, mytomycin and anthracyclines, such as doxorubicin, daunorubicin, valrubicin, idarubicin, epirubicin, and antibody treatments, such as abciximab, adamlimumab, alamtuzumab, basiliximab, belimumab, bevacizumab, brentuximab vedotin, canakinumab, cetuximab, certolizumab pego, daclizumab, denosumab, eculizumab, efalizumab, gemtuzumab, golimumab, ibritumomab tiuxetan, infliximab, ipilimumab, muromonab-CD3, natalizumab, ofatumumab, omalizumab, palivizumab, panitumumab, ranibizumab, rituximab, tocilizumab (atlizumab), tositumomab and trastuzumab.

The terms “anti-inflammatory” and “anti-inflammatory agent” are also used interchangeably herein, and mean and include a “pharmacological agent” and/or “active agent formulation”, which, when a therapeutically effective amount is administered to a subject, prevents or treats bodily tissue inflammation i.e. the protective tissue response to injury or destruction of tissues, which serves to destroy, dilute, or wall off both the injurious agent and the injured tissues.

Anti-inflammatory agents thus include, without limitation, alclofenac, alclometasone dipropionate, algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenac sodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazide disodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains, broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasone butyrate, clopirac, cloticasone propionate, cormethasone acetate, cortodoxone, decanoate, deflazacort, delatestryl, depo-testosterone, desonide, desoximetasone, dexamethasone dipropionate, diclofenac potassium, diclofenac sodium, diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen, fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasol propionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole, intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam, loteprednol etabonate, meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone, mesterolone, methandrostenolone, methenolone, methenolone acetate, methylprednisolone suleptanate, momiflumate, nabumetone, nandrolone, naproxen, naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein, orpanoxin, oxandrolane, oxaprozin, oxyphenbutazone, oxymetholone, paranyline hydrochloride, pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazole citrate, rimexolone, romazarit, salcolex, salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin, stanozolol, sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide, testosterone, testosterone blends, tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium, triclonide, triflumidate, zidometacin, and zomepirac sodium.

The term “pharmacological composition”, as used herein, means and includes a composition comprising a “pharmacological agent” and/or a “biologically active agent” and/or any additional agent or component identified herein.

The term “therapeutically effective”, as used herein, means that the amount of the “pharmacological composition” and/or “pharmacological agent” and/or “biologically active agent” administered is of sufficient quantity to ameliorate one or more causes, symptoms, or sequelae of a disease or disorder. Such amelioration only requires a reduction or alteration, not necessarily elimination, of the cause, symptom, or sequelae of a disease or disorder.

The terms “prevent” and “preventing” are used interchangeably herein, and mean and include reducing the frequency or severity of a disease or condition. The term does not require an absolute preclusion of the disease or condition. Rather, this term includes decreasing the chance for disease occurrence.

The terms “treat” and “treatment” are used interchangeably herein, and mean and include medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder. The terms include “active treatment”, i.e. treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and “causal treatment”, i.e. treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.

The terms “treat” and “treatment” further include “palliative treatment”, i.e. treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder, “preventative treatment”, i.e. treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder, and “supportive treatment”, i.e. treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.

The terms “patient” and “subject” are used interchangeably herein, and mean and include warm blooded mammals, humans and primates; avians; domestic household or farm animals, such as cats, dogs, sheep, goats, cattle, horses and pigs; laboratory animals, such as mice, rats and guinea pigs; fish; reptiles; zoo and wild animals; and the like.

The term “comprise” and variations of the term, such as “comprising” and “comprises,” means “including, but not limited to” and is not intended to exclude, for example, other additives, components, integers or steps.

The following disclosure is provided to further explain in an enabling fashion the best modes of performing one or more embodiments of the present invention. The disclosure is further offered to enhance an understanding and appreciation for the inventive principles and advantages thereof, rather than to limit in any manner the invention. The invention is defined solely by the appended claims, including any amendments made during the pendency of this application, and all equivalents of those claims as issued.

As stated above, it is understood that, although the present invention is described and illustrated in connection with encased medical devices, the invention is not limited to medical devices. According to the invention, the extracellular matrix (ECM) structures and compositions of the invention can also be employed to encase other devices, including, by way of example, a sensor or tracking device.

It is also understood that, although the present invention is described and illustrated in connection with a pacemaker, the invention is not limited to the noted medical device. Indeed, as stated above, the ECM encasement structures and compositions of the invention can also be employed to encase other medical devices, including without limitation, a defibrillator, synthetic heart valve, ventricular assist device, artificial heart, physiological sensor, catheter, and associated components thereof, including electrical leads and lines associated therewith.

As discussed above, in one embodiment, the present invention is directed to encasement structures and compositions for encasing medical devices.

In a preferred embodiment, the encasement structures comprise (or are constructed of) a bioremodelable member comprising a bioremodelable composition that includes at least one ECM material (hereinafter “ECM encasement structures”). In some embodiments of the invention, the encasement structures comprise a plurality of bioremodelable members.

As discussed in detail herein, in a preferred embodiment of the invention, the encasement structures of the invention comprise a pouch or pocket that is configured to receive and, hence, encase a medical device therein.

According to the invention, the medical device can comprise, without limitation, a pacemaker, defibrillator, synthetic heart valve, ventricular assist device, artificial heart, physiological sensor, catheter, and the electrical leads and lines associated therewith.

According to the invention, the encasement structures and, hence, pouches thereof, can also comprise various shapes and sizes to accommodate virtually all shapes and sizes of medical devices.

The bioremodelable member(s) can also comprise a substantially solid or mesh structure. Suitable mesh structures are set forth in Co-Pending application Ser. No. 14/554,730, filed on Nov. 26, 2014, which is incorporated by reference herein in its entirety.

As indicated above, in a preferred embodiment, the encasement structures comprise (or are constricted of) a bioremodelable member comprising a bioremodelable composition that includes at least one ECM material.

According to the invention, the ECM material can be derived from various mammalian tissue sources and methods for preparing same, such as disclosed in U.S. Pat. Nos. 7,550,004, 7,244,444, 6,379,710, 6,358,284, 6,206,931, 5,733,337 and 4,902,508 and U.S. application Ser. No. 12/707,427; which are incorporated by reference herein in their entirety. The mammalian tissue sources include, without limitation, the small intestine, large intestine, stomach, lung, liver, kidney, pancreas, placenta, heart, bladder, prostate, tissue surrounding growing enamel, tissue surrounding growing bone, and any fetal tissue from any mammalian organ.

The mammalian tissue sources can thus comprise, without limitation, small intestine submucosa (SIS), urinary bladder submucosa (UBS), stomach submucosa (SS), central nervous system tissue, epithelium of mesodermal origin, i.e. mesothelial tissue, dermal extracellular matrix, subcutaneous extracellular matrix, gastrointestinal extracellular matrix, i.e. large and small intestines, tissue surrounding growing bone, placental extracellular matrix, ornamentum extracellular matrix, cardiac extracellular matrix, e.g., pericardium and/or myocardium, kidney extracellular matrix, pancreas extracellular matrix, lung extracellular matrix, and combinations thereof. The ECM can also comprise collagen from mammalian sources.

In some embodiments, the mammalian tissue source comprises mesothelial tissue.

In a preferred embodiment, the mammalian tissue source comprises an adolescent mammalian tissue source, i.e. mammalian tissue from a mammal less than 3 years of age.

The ECM can also be derived from the same or different mammalian tissue sources, as disclosed in Co-Pending application Ser. Nos. 13/033,053 and 13/033,102; which are incorporated by reference herein.

According to the invention, the ECM material can be used in whole or in part, so that, for example, an ECM material can contain just the basement membrane (or transitional epithelial layer) with the subjacent tunica propria, the tunica submucosa, tunica muscularis, and tunica serosa. The ECM material component of the composition can contain any or all of these layers, and thus could conceivably contain only the basement membrane portion, excluding the submucosa. However, generally, and especially since the submucosa is thought to contain and support the active growth factors and other proteins necessary for in vivo tissue regeneration, the ECM or matrix composition from any given source will contain the active extracellular matrix portions that support cell development and differentiation and tissue regeneration.

According to the invention, the ECM material can comprise mixed solid particulates. The ECM material can also be formed into a particulate and fluidized, as described in U.S. Pat. Nos. 5,275,826, 6,579,538 and 6,933,326, to form a mixed emulsion, mixed gel or mixed paste.

The ECM material can also be sterilized via applicant's proprietary sterilization (i.e. Novasterillis®) process, as disclosed in Co-Pending U.S. application Ser. No. 13/480,205; which is expressly incorporated herein in their entirety.

As indicated above, in some embodiments of the invention, the bioremodelable compositions and/or materials and, hence, encasement structures formed therefrom, include at least one additional biologically active agent or composition, i.e. an agent that induces or modulates a physiological or biological process, or cellular activity, e.g., induces proliferation, and/or growth and/or regeneration of tissue.

Suitable biologically active agents include any of the aforementioned biologically active agents, including, without limitation, the aforementioned cells, proteins and growth factors.

In some embodiments, the bioremodelable compositions and/or materials and, hence, encasement structures formed therefrom, include at least one pharmacological agent or composition (or drug), i.e. an agent or composition that is capable of producing a desired biological effect in vivo, e.g., stimulation or suppression of apoptosis, stimulation or suppression of an immune response, etc.

Suitable pharmacological agents and compositions include any of the aforementioned agents, including, without limitation, antibiotics, anti-viral agents, analgesics, steroidal anti-inflammatories, non-steroidal anti-inflammatories, anti-neoplastics, anti-spasmodics, modulators of cell-extracellular matrix interactions, proteins, hormones, enzymes and enzyme inhibitors, anticoagulants and/or antithrombic agents, DNA, RNA, modified DNA and RNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, polypeptides, oligonucleotides, polynucleotides, nucleoproteins, compounds modulating cell migration, compounds modulating proliferation and growth of tissue, and vasodilating agents.

In some embodiments of the invention, the pharmacological agent comprises a statin, i.e. a HMG-CoA reductase inhibitor. According to the invention, suitable statins include, without limitation, atorvastatin (Lipitor®), cerivastatin, fluvastatin (Lescol®), lovastatin (Mevacor®, Altocor®, Altoprev®), mevastatin, pitavastatin (Livalo®, Pitava®), pravastatin (Pravachol®, Selektine®, Lipostat®), rosuvastatin (Crestor®), and simvastatin (Zocor®, Lipex®). Several actives comprising a combination of a statin and another agent, such as ezetimbe/simvastatin (Vytorin®), are also suitable.

Applicant has found that the noted statins exhibit numerous beneficial properties that provide several beneficial biochemical actions or activities. The properties and beneficial actions are set forth in Applicant's Co-Pending application Ser. No. 13/373,569, filed on Sep. 24, 2012 and Ser. No. 13/782,024, filed on Mar. 1, 2013; which are incorporated by reference herein in their entirety.

Additional suitable pharmacological agents and compositions that can be delivered within the scope of the invention are disclosed in U.S. Pat. Pub. Nos. 20070014874, 20070014873, 20070014872, 20070014871, 20070014870, 20070014869, and 20070014868; which are expressly incorporated by reference herein in its entirety.

According to the invention, the biologically active and pharmacological agents referenced above can comprise various forms. In some embodiments of the invention, the biologically active and pharmacological agents, e.g. simvastatin, comprise microcapsules that provide delayed delivery of the agent contained therein.

In some embodiments of the invention, the biologically active agent comprises a protein selected from the group comprising, without limitation, collagen (types I-V), proteoglycans, glycosaminoglycans (GAGs), glycoproteins, cytokines, cell-surface associated proteins, and cell adhesion molecules (CAMs).

In some embodiments, the biologically active agent provides a structural support scaffold comprising at least one layer. Suitable bioactive agents include, without limitation, elastin and ECM having additional GAG content, such as additional hyaluronic acid and/or chondroitin sulfate.

In some embodiments of the invention, the bioremodelable compositions and/or materials comprise a single-stage agent delivery profile, i.e. a single-stage delivery vehicle, wherein a modulated dosage of an aforementioned biologically active and/or pharmacological agent is provided.

According to the invention, the term “modulated dosage” as used herein, and variants of this language generally refer to the modulation (e.g., alteration, delay, retardation, reduction, etc.) of a process involving different eluting or dispersal rates of an agent within biological tissue.

In some embodiments, the single-stage delivery profile comprises and, hence, is provided (or induced) by encapsulated particulates of the biologically active and/or pharmacological agent having a tailored degradation profile.

In some embodiments, the encapsulation composition comprises an ECM composition.

In some embodiments, the encapsulation composition comprises a biodegradable polymer composition, including without limitation, an aforementioned hydrogel, polyglycolide (PGA), polylactide (PLA), polyepsilon-caprolactone, poly-dioxanone, poly lactide-co-glycolide polysaccharides (e.g. starch and cellulose) and proteins (e.g., gelatin, casein, silk, wool, etc.).

In some embodiments, the encapsulation composition comprises an osmotic fluctuation inducing compound including, without limitation, polyethylene glycol, alginate and dextran.

According to the invention, the term “osmotic fluctuation” as used herein, and variants of this language generally refer to the modulation of the osmotic pressure gradient across a defined barrier.

For example, as is well known in the art, alginate is capable of absorbing 200-300 times its weight in water and, thus, substantially increases the osmotic pressure gradient upon exposure to water. The increased osmotic pressure gradient results in rapid dispersal of an agent therefrom via the pressure gradient.

In some embodiments of the invention, the bioremodelable “ECM” compositions comprise a multi-stage agent delivery profile, i.e. a multi-stage delivery vehicle, wherein a plurality of the aforementioned biologically active and/or pharmacological agents is administered via a modulated dosage. By way of example, in some embodiments, the multi-stage agent delivery vehicle comprises an antibiotic composition encapsulated in an alginate having a statin incorporated therein, which provides a tiered modulated dosage delivery profile.

In some embodiments, the multi-stage agent delivery vehicle comprises a plurality of different biologically active and/or pharmacological agents encapsulated in different encapsulation compositions. By way of example, in some embodiments, the multi-stage delivery vehicle comprises a growth factor encapsulated in a first encapsulation composition, e.g., an alginate composition, having a first agent delivery profile that is concomitantly administered with an anti-inflammatory that is encapsulated in a second encapsulation composition, e.g., a polyglycolide composition, having a second agent delivery profile.

According to the invention, upon deployment of an encasement structure of the invention and, hence, a medical device encased therein, to damaged and/or diseased biological tissue, “modulated healing” is effectuated.

The term “modulated healing”, as used herein, and variants of this language generally refer to the modulation (e.g., alteration, delay, retardation, reduction, etc.) of a process involving different cascades or sequences of naturally occurring tissue repair in response to localized tissue damage or injury, substantially reducing their inflammatory effect. Modulated healing, as used herein, includes many different biologic processes, including epithelial growth, fibrin deposition, platelet activation and attachment, inhibition, proliferation and/or differentiation, connective fibrous tissue production and function, angiogenesis, and several stages of acute and/or chronic inflammation, and their interplay with each other.

For example, in some embodiments, an encasement structure of the invention is specifically formulated (or designed) to alter, delay, retard, reduce, and/or detain one or more of the phases associated with healing of damaged tissue, including, but not limited to, the inflammatory phase (e.g., platelet or fibrin deposition), and the proliferative phase when in contact with biological tissue.

In some embodiments, “modulated healing” refers to the ability of an encasement structure to alter a substantial inflammatory phase (e.g., platelet or fibrin deposition) at the beginning of the tissue healing process. As used herein, the phrase “alter a substantial inflammatory phase” refers to the ability of an encasement structure to substantially reduce the inflammatory response at an injury site when in contact with biological tissue.

In such an instance, a minor amount of inflammation may ensue in response to tissue injury, but this level of inflammation response, e.g., platelet and/or fibrin deposition, is substantially reduced when compared to inflammation that takes place in the absence of an encasement structure of the invention.

By way of example, the encasement structures discussed herein have been shown experimentally to delay or alter the inflammatory response associated with damaged tissue, as well as excessive formation of connective fibrous tissue following tissue damage or injury. The encasement structures have also been shown experimentally to delay or reduce fibrin deposition and platelet attachment to a blood contact surface following tissue damage.

In some embodiments of the invention, “modulated healing” refers to the ability of an encasement structure of the invention to induce host tissue proliferation, bioremodeling, including neovascularization, e.g., vasculogenesis, angiogenesis, and intussusception, and regeneration of tissue structures with site-specific structural and functional properties.

In some embodiments, when an encasement structure is in contact with biological tissue modulated healing is effectuated through the structural features of the encasement structure. The structural features provide the spatial temporal and mechanical cues to modulate cell polarity and alignment. The structural features further modulate cell proliferation, migration and differentiation.

In some embodiments of the invention, the encasement structures comprise a biocompatible polymeric composition.

According to the invention, the polymeric composition can comprise, without limitation, polyglycolide (PGA), polylactide (PLA), polyepsilon-caprolactone, poly dioxanone (a polyether-ester), poly lactide-co-glycolide, polyamide esters, polyalkalene esters, polyvinyl esters, polyvinyl alcohol, and polyanhydrides. Natural polymeric materials, include, without limitation, polysaccharides (e.g. starch and cellulose), proteins (e.g., gelatin, casein, silk, wool, etc.), and polyesters (e.g., polyhydroxyalkanoates).

The polymeric composition can also comprise a hydrogel including, without limitation, polyurethane, poly(ethylene glycol), polypropylene glycol), poly(vinylpyrrolidone), xanthan, methyl cellulose, carboxymethyl cellulose, alginate, hyaluronan, poly(acrylic acid), polyvinyl alcohol, acrylic acid, hydroxypropyl methyl cellulose, methacrylic acid, αβ-glycerophosphate, κ-carrageenan, 2-acrylamido-2-methylpropanesulfonic acid, and β-hairpin peptide.

In some embodiments, the hydrogel is crosslinked via chemically and/or photocuring, e.g. ultraviolet light.

In some embodiments, the polymeric composition includes at least one of the aforementioned biologically active or pharmacological agents.

Thus, in some embodiments of the invention, when a polymeric encasement structure of the invention is administered to damaged and/or diseased biological tissue, “modulated healing” is similarly effectuated.

As indicated above, in some embodiments, the encasement structures comprise at least one coating. In some embodiments, the coating includes at least one of the aforementioned biologically active and/or pharmacological agents.

In some embodiments of the invention, the coating similarly provides a single-stage agent delivery profile, such as discussed above. In some embodiments, the coating provides a multi-stage agent delivery profile.

In some embodiments, the encasement structures comprise a plurality of coatings comprising the same or a substantially similar coating composition. In some embodiments, the encasement structures comprise a plurality of coatings comprising different coating compositions having different biologically active or pharmacological agents and, hence, properties.

In some embodiments, the encasement structure coatings comprise an ECM composition that similarly comprises at least one ECM material (hereinafter “ECM coatings”).

According to the invention, suitable ECM compositions comprising ECM and biologically active and pharmacological agents are disclosed in U.S. Pat. Nos. 8,568,761, 8,753,885, 8,795,728, 8,734,841, 8,642,084, 8,771,737, 8,734,842, 8,784,891, 8,753,886, 8,785,197, 8,785,198, 8,735,155 and U.S. patent application Ser. No. 13/732,943, filed on Jan. 2, 2013, Ser. No. 11/448,351, filed on Jun. 6, 2006, Ser. No. 14/269,324, filed on May 5, 2014, Ser. No. 13/732,558, filed on Jan. 2, 2013, Ser. No. 13/732,731, filed on Jan. 2, 2013, Ser. No. 13/875,017, filed on May 1, 2013, Ser. No. 13/875,043, filed on May 1, 2013, Ser. No. 13/875,058, filed on May 1, 2013, Ser. No. 14/452,707, filed on Aug. 6, 2014, Ser. No. 14/192,973, filed on Jan. 28, 2014, Ser. No. 14/192,992, filed on Feb. 28, 2014, Ser. No. 14/193,008, filed on Feb. 28, 2014, Ser. No. 14/193,030, filed on Feb. 28, 2014, Ser. No. 14/193,053, filed on Feb. 28, 2014, Ser. No. 14/269,414, filed on Mar. 3, 2013, Ser. No. 14/269,487, filed on Mar. 3, 2013, Ser. No. 14/269,874, filed on Mar. 3, 2013, Ser. No. 14/337,460, filed on Mar. 3, 2013; which are incorporated by reference herein in their entirety.

Suitable ECM compositions are also disclosed in Co-Pending application Ser. No. 14/554,730.

In some embodiments, the ECM coatings are configured to provide various biologically active and/or pharmacological agent delivery profiles.

In some embodiments, the ECM coatings are configured to provide a gradient of various biologically active and/or pharmacological agent delivery profiles. By way of example, in some embodiments, the biologically active and/or pharmacological agents are disposed throughout various depths or thickness ranges of the ECM coating.

In some embodiments of the invention, wherein the encasement structures comprise a plurality of ECM coatings, the plurality of ECM coatings is similarly configured to provide various biologically active and/or pharmacological agent delivery profiles. By way of example, in some embodiments, the encasement structures comprise a first coating comprising a growth factor augmented ECM composition and a second coating comprising an ECM composition comprising a pharmacological agent, such as an anti-inflammatory or antiviral.

In some embodiments, the ECM coatings comprise interleukin-10 (IL-10) and transforming growth factor beta (TGF-β) alone, or in combination, to suppress the inflammatory reaction leading to a chronic immune response, thus, augmenting or enhancing “modulated healing”. During the chronic immune response, IL-10 and TGF-β induce the expression of tissue inhibitor of metalloproteinase (TIMP), which inhibits the matrix metalloproteinases (MMPs) responsible for ECM degradation during the inflammatory response. Additionally, IL-10 and TGF-β promote the recruitment of fibroblasts, which are the seminal cells responsible for ECM deposition and bioremodeling. As a result, IL-10, TGF-β, and the TIMPs concomitantly promote ECM deposition and preservation, which thus augment “modulated healing.”

In some embodiments, the ECM coatings comprise a pharmacological agent, such as an anti-inflammatory or antiviral, which provide a reinforcing anti-inflammatory effect either through direct reinforcement, i.e. targeting the same inflammatory signaling pathway, or indirect reinforcement, i.e. targeting an alternate inflammatory signaling pathway. An example of direct reinforcement includes, without limitation, a combination of IL-10, TGF-β and a glucocorticoid, all of which inhibit the expression of seminal inflammatory cytokine interleukin-1 (IL-1). An example of indirect reinforcement includes, without limitation, a combination of IL-10, TGF-β and an NSAID, (Non-steroidal anti-inflammatory drug) where IL-10 and TGF-β inhibit IL-1, and the NSAIDs inhibit the activity of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and thereby, the synthesis of prostaglandins and thromboxanes.

Thus, in some embodiments of the invention, when an encasement structure coated with an ECM composition of the invention is administered to damaged and/or diseased biological tissue, “modulated healing” is similarly enhanced.

In some embodiments, the encasement structure coatings comprise a polymeric composition. In some embodiments, the encasement structure comprises a plurality of polymeric coatings.

According to the invention, suitable polymeric compositions are set forth in U.S. application Ser. Nos. 14/566,155, 14/566,306, 14/566,359 and 14/566,209 filed on Nov. 26, 2014; which are incorporated by reference herein in their entirety.

In some embodiments, the polymeric coating(s) are similarly configured to provide various biologically active and/or pharmacological agent delivery profiles. Again, by way of example, the encasement structures of the invention can comprise a first polymeric coating comprising a growth factor augmented polymeric composition and a second polymeric coating comprising a polymeric composition comprising a pharmacological agent, such as an anti-inflammatory or antiviral.

According to the invention, the coatings can additionally comprise a hydrogel, including, without limitation, polyurethane, poly(ethylene glycol), polypropylene glycol), poly(vinylpyrrolidone), xanthan, methyl cellulose, carboxymethyl cellulose, alginate, hyaluronan, poly(acrylic acid), polyvinyl alcohol, acrylic acid, hydroxypropyl methyl cellulose, methacrylic acid, αβ-glycerophosphate, κ-carrageenan, 2-acrylamido-2-methylpropanesulfonic acid, and β-hairpin peptide.

In some embodiments, the coatings comprise a blend of the aforementioned ECM and polymeric materials.

In a preferred embodiment, the polymer/ECM blended coating(s) are similarly configured to provide various biologically active and/or pharmacological agent delivery profiles.

In some embodiments of the invention, the coatings comprise an ECM-mimicking biomaterial composition, such as disclosed in Co-Pending U.S. application Ser. Nos. 14/566,404 and 14/566,155, filed on Dec. 10, 2014; which are expressly incorporated by reference herein in their entirety. In a preferred embodiment of the invention, the ECM-mimicking biomaterial composition comprises poly(glycerol sebacate) (PGS).

In another embodiment of the invention, there is provided a medical device (or instrument) that includes at least one of the aforementioned coatings.

According to the invention, upon implanting one of the aforementioned encasement structures; particularly, an ECM encasement structure, having a medical device therein or a medical device (or instrument) coated with an ECM composition or biologically active or pharmacological agent augmented polymer composition of the invention to or in a subject, modulated healing is similarly induced.

Referring now to FIG. 1, there is shown an exemplar implantable medical device; in this instance, a bi-ventricular (Bi-V) pacemaker 10, that can be encased by an encasement structure of the invention. As is well known in the art and illustrated in FIG. 1, the Bi-V pacemaker 10 generally includes a pulse generator 11, electrical leads 12 a, 12 b, 12 c and lead tips or electrodes 14 a, 14 b, 14 c.

As is also well known in the art, the Bi-V pacemaker 10 is used to modulate the heart rate of a patient and prevent a life threatening heart dysfunction, e.g. arrhythmia.

The Bi-V pacemaker 10 is typically implanted transveniously in a patient, wherein two (2) electrical leads, i.e. leads 12 a, 12 b, are placed in a vein and guided to the right atrium and ventricle of the heart. The leads 12 a, 12 b are then attached to the heart muscle proximate the noted heart structures.

The third pacemaker lead, i.e., lead 12 c, is also guided through a vein to the coronary sinus (i.e. a small vein on the back of the heart) and attached to the heart to pace the left ventricle.

Referring now to FIG. 2A, there is shown one embodiment of a bioremodelable member 20 a of the invention. According to the invention, the bioremodelable member 20 a can comprise a substantially solid sheet of bioremodelable material, i.e. a sheet structure, 20 a′, as shown in FIG. 2A.

The bioremodelable member 20 a can also comprise a mesh structure 20 a″, such as shown in FIG. 2B.

As discussed in detail herein, in a preferred embodiment, the bioremodelable member 20 a comprises a bioremodelable composition that includes at least one of the aforementioned ECM materials.

In some embodiments of the invention, the ECM material and, hence bioremodelable member 20 a formed therefrom, includes at least one additional biologically active agent or composition, i.e. an agent that induces or modulates a physiological or biological process, or cellular activity, e.g., induces proliferation, and/or growth and/or regeneration of tissue.

In some embodiments, the biologically active agent comprises a growth factor selected from the group comprising transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β), fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor (bFGF), and vascular epithelial growth factor (VEGF).

In some embodiments, the biologically active agent comprises a cell selected from the group comprising a stem cell, cardiomyocyte, myofibroblast, mesenchymal stem cell, exogenous cell, endogenous cell, progenitor cell and macrophage.

In some embodiments of the invention, the ECM material and, hence bioremodelable member 20 a formed therefrom, includes at least one pharmacological agent or composition (or drug), i.e. an agent or composition that is capable of producing a desired biological effect in vivo, e.g., stimulation or suppression of apoptosis, stimulation or suppression of an immune response, etc.

In some embodiments, the pharmacological agent or composition is selected from the group comprising an antibiotic, antifungal agent, anti-viral agent, anticoagulant, antithrombic agent and anti-inflammatory.

In some embodiments of the invention, the pharmacological agent comprises a statin, i.e. a HMG-CoA reductase inhibitor, selected from the group comprising atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.

Referring now to FIG. 3, in some embodiments, the bioremodelable member 20 a comprises at least one coating or outer layer 22.

According to the invention, the coating 22 can be disposed on a defined region of the bioremodelable member 20 a, such as the top surface 21 (as shown in FIG. 3) or the entire outer surface 23 (as shown in FIG. 4). The coating 22 can also be disposed on the outer surface 23 in a predetermined pattern, such as a plurality of dots or lines.

In some embodiments, the coating 22 comprises a pharmacological agent or composition, i.e. a composition comprising one of the aforementioned pharmacological agents.

In some embodiments, the coating 22 comprises one of the aforementioned ECM compositions.

In some embodiments of the invention, the coating 22 comprises one of the aforementioned polymeric compositions.

Referring now to FIG. 5, there is shown a perspective view of bioremodelable member 20 a in a folded pre-lamination configuration. According to the invention, to form an encasement structure or pouch 30 a of the invention, the bioremodelable member 20 a is folded over (preferably, proximate the mid region thereof) and laminated on at least end 16, more preferably, the bioremodelable member 20 a is laminated on end 16 and sides 18, wherein a cavity, such as cavity 32 shown in FIG. 9, is formed therein.

According to the invention, the end 16 and sides 18 of the bioremodelable member 20 a can be laminated by various conventional means, such as stitching, including ECM stitches, stapled, adhesives. The end 16 and sides 18 of the bioremodelable member 20 a can also be laminated via microneedles and/or microneedle structures, such as disclosed in Co-Pending application Ser. No. 13/686,131.

Referring now to FIG. 6, there is shown another embodiment of a bioremodelable member that can be employed to form a curved or round encasement structure of the invention. As illustrated in FIG. 6, the bioremodelable member 20 b comprises an integral sheet member having two similar circular ends 24 a, 24 b.

Referring now to FIG. 7, there is shown a perspective view of bioremodelable member 20 b in a folded pre-lamination configuration. According to the invention, to form an encasement structure or pouch of the invention, the bioremodelable member 20 b is folded proximate region 25 and the edges 27 a, 27 b of the circular ends 24 a, 24 b are laminated, wherein the encasement structure 30 a shown in FIG. 9 is formed. As illustrated in FIG. 9, the encasement structure 30 a includes an internal cavity 32.

Referring now to FIGS. 8 and 9, there are shown illustrations of pacemaker 10 positioned (i.e. encased) in cavity 32 of encasement structure 30 a. As illustrated in FIG. 8, the encasement structure 30 a is preferably configured to encase the entire pacemaker 10 and at least a portion of the leads 12 a, 12 b, 12 c associated therewith.

Referring now to FIG. 10, in some embodiments of the invention, two (2) bioremodelable members 20 c, 20 d are employed to form an encasement structure 30 b that is similarly configured to encase the entire pacemaker 10 and at least a portion of the leads 12 a, 12 b, 12 c associated therewith. In a preferred embodiment, the bioremodelable members 20 c, 20 d have a shape that is similar to the ends 24 a, 24 b of bioremodelable member 20 b shown in FIG. 6.

According to the invention, to form encasement structure 30 b, the bioremodelable members 20 c, 20 d are laminated about the respective outer edges 29 a, 29 b, forming cavity 33 therein.

Referring now to FIGS. 11 and 12, there is shown a medical device, in this instance, Bi-V pacemaker 10, discussed above, having a coating 42 disposed thereon. In this instance, the coating 42 comprises an ECM composition.

According to the invention, at least a portion of the pacemaker 10 is coated with the ECM composition coating 42. In a preferred embodiment, the entire pacemaker 10 is coated with the ECM composition coating 42.

In some embodiments, the entire pacemaker 10 and electrical leads associated therewith, e.g. leads 12 a, 12 b, 12 c, are coated with the ECM composition coating 42.

According to the invention, various conventional means can be employed to form the coated biocompatible and hemocompatable medical device (and associated leads), including spray coating, dipping, etc.

As indicated above, upon implanting an encasement structure comprising a bioremodelable composition; particularly, an ECM composition and/or a polymer composition that is augmented with a biologically active or pharmacological agent and, hence, a medical device encased therein or a medical device (or instrument) coated with an ECM composition and/or a polymer composition that is augmented with a biologically active or pharmacological agent to or in a subject, modulated healing, including modulation of at least one inflammatory phase and regeneration of tissue and tissue structures with site-specific structural and functional properties, is induced.

As will readily be appreciated by one having ordinary skill in the art, the present invention provides numerous advantages. Among the advantages are the following:

-   -   The provision of encasement structures that are configured to         encase a medical device therein and that substantially reduce or         eliminate the harsh biological responses associated with         conventional implanted medical devices, including inflammation,         infection and thrombogenesis, when implanted in the body.     -   The provision of encasement structures that are configured to         encase a medical device therein, and effectively improve         biological functions and/or promote modulated healing of         adjacent tissue and the growth of new tissue when implanted in         the body.     -   The provision of encasement structures that are configured to         encase a medical device therein and administer one or more         pharmacological or therapeutic agents to a subject when         implanted in his/her body.     -   The provision of encasement structures that are configured to         encase a medical device therein and provide single and         multi-stage agent delivery profiles.     -   The provision of medical device coatings that provide single and         multi-stage agent delivery profiles.     -   The provision of coated medical devices that are configured for         insertion or implantation in the body and exhibit enhanced         biocompatibility and hemocompatibility when inserted or         implanted therein.     -   The provision of coated medical devices that substantially         reduce or eliminate the harsh biological responses associated         with conventional implanted medical devices, including         inflammation, infection and thrombogenesis, when implanted in         the body.     -   The provision of coated medical devices that are configured to         administer one or more pharmacological or therapeutic agents to         a subject when implanted in his/her body.

Without departing from the spirit and scope of this invention, one of ordinary skill can make various changes and modifications to the invention to adapt it to various usages and conditions. As such, these changes and modifications are properly, equitably, and intended to be, within the full range of equivalence of any subsequently proffered claims. 

What is claimed is:
 1. A bioremodelable encasement structure, comprising: a bioremodelable encasement structure formed from at least one sheet member comprising a bioremodelable extracellular matrix (ECM) composition, said encasement structure having an outer surface and internal region configured to receive a device therein, said ECM composition comprising at least one acellular ECM material selected from the group consisting of small intestine submucosa (SIS), urinary bladder submucosa (UBS), urinary basement membrane (UBM), liver basement membrane (LBM), mesothelial tissue, placental extracellular matrix, and heart extracellular matrix, said encasement structure further comprising a coating disposed on at least a portion of said outer surface, said coating comprising a pharmacological agent selected from the group consisting of an anti-microbial agent, hemostatic agent and anti-inflammatory.
 2. The encasement structure of claim 1, wherein said sheet member comprises a mesh structure.
 3. The encasement structure of claim 1, wherein said anti-microbial agent is selected from the group consisting of actinomyocin, bleomycin, plicamycin, mytomycin anthracyclines, neomycin, polymyxin b, bacitracin, gramicidin, gentamicin, oyxtetracycline, ciprofloxacin, ofloxacin, tobramycin, amikacin, vancomycin, cefazolin, ticarcillin, and chloramphenicol.
 4. The encasement structure of claim 1, wherein said hemostatic agent is selected from the group consisting of a platlet derived growth factor (PDGF), fibronectin and chitosan.
 5. The encasement structure of claim 1, wherein said ECM composition includes an additional biologically active agent.
 6. The encasement structure of claim 5, wherein said biologically active agent comprises a growth factor selected from the group consisting of transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β), fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor (bFGF), and vascular epithelial growth factor (VEGF).
 7. The encasement structure of claim 5, wherein said biologically active agent comprises a cell selected from the group consisting of a stem cell, cardiomyocyte, myofibroblast, mesenchymal stem cell, progenitor cell and macrophage.
 8. The encasement structure of claim 5, wherein said biologically active agent comprises a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.
 9. The encasement structure of claim 1, wherein said device comprises a medical device selected from the group consisting of a pacemaker, defibrillator and ventricular assist device.
 10. A bioremodelable encasement structure, comprising: a bioremodelable encasement structure formed from at least one sheet member comprising a bioremodelable extracellular matrix (ECM) composition, said encasement structure having an outer surface and internal region configured to receive a device therein, said ECM composition comprising at least one acellular ECM material selected from the group consisting of small intestine submucosa (SIS), urinary bladder submucosa (UBS), urinary basement membrane (UBM), liver basement membrane (LBM), mesothelial tissue, placental extracellular matrix, and heart extracellular matrix, said encasement structure further comprising a coating disposed on at least a portion of said outer surface, said coating comprising an ECM-mimicking biomaterial composition comprising poly(glycerol sebacate) (PGS).
 11. The encasement structure of claim 1, wherein said ECM-mimicking biomaterial composition further comprises an anti-microbial agent selected from the group consisting of actinomyocin, bleomycin, plicamycin, mytomycin anthracyclines, neomycin, polymyxin b, bacitracin, gramicidin, gentamicin, oyxtetracycline, ciprofloxacin, ofloxacin, tobramycin, amikacin, vancomycin, cefazolin, ticarcillin, and chloramphenicol.
 12. The encasement structure of claim 1, wherein said ECM-mimicking biomaterial composition further comprises a hemostatic agent selected from the group consisting of a platlet derived growth factor (PDGF), fibronectin and chitosan.
 13. The encasement structure of claim 1, wherein said ECM composition includes an additional biologically active agent.
 14. The encasement structure of claim 13, wherein said biologically active agent comprises a growth factor selected from the group consisting of transforming growth factor alpha (TGF-α), transforming growth factor beta (TGF-β), fibroblast growth factor-2 (FGF-2), basic fibroblast growth factor (bFGF), and vascular epithelial growth factor (VEGF).
 15. The encasement structure of claim 13, wherein said biologically active agent comprises a cell selected from the group consisting of a stem cell, cardiomyocyte, myofibroblast, mesenchymal stem cell, progenitor cell and macrophage.
 16. The encasement structure of claim 13, wherein said biologically active agent comprises a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin.
 17. The encasement structure of claim 13, wherein said device comprises a medical device selected from the group consisting of a pacemaker, defibrillator and ventricular assist device.
 18. A bioremodelable encasement structure, comprising: a bioremodelable encasement structure formed from at least one sheet member comprising a bioremodelable extracellular matrix (ECM) composition, said encasement structure having an outer surface and internal region configured to receive a device therein, said ECM composition comprising at least one acellular ECM material selected from the group consisting of small intestine submucosa (SIS), urinary bladder submucosa (UBS), urinary basement membrane (UBM), liver basement membrane (LBM), mesothelial tissue, placental extracellular matrix, and heart extracellular matrix, said encasement structure further comprising a coating disposed on at least a portion of said outer surface, said coating comprising a polymeric material composition comprising at least one biodegradable polymeric material selected from the group consisting of polyhydroxyalkonates (PHAs), polylactides (PLLA) and polyglycolides (PLGA), polyanhydrides and homopolymers and copolymers of poly(lactic acid) and poly(glycolic acid), and copolyesters of e-caprolactone. 